在联合癌症免疫治疗领域，针对癌细胞和巨噬细胞的治疗策略组合具有巨大的潜力。然而，主要挑战仍然是如何实现这些疗法的便捷时空递送，从而易于操作并确保差异药物释放以增强协同治疗效果。在本研究中，我们引入了一种适应肿瘤微环境（TME）的水凝胶，以苯基硼酸修饰的双嘧达莫前药（DIPP）作为交联剂。这种前药水凝胶支架 3BP@DIPPGel 可以通过 DIPP 和聚乙烯醇 (PVA) 的简单混合物原位形成，并负载高比例的 3-溴丙酮酸 (3BP)。 3BP@DIPPGel 能够以独特的释放动力学对双嘧达莫 (DIP) 和 3BP 进行时空局部递送，从而有效地重塑免疫抑制性 TME。在活性氧 (ROS) 刺激下，3BP@DIPPGel 优先释放 3BP，通过 ROS/BAX/caspase-3/GSDME 信号通路诱导肿瘤特异性焦亡，并减少 CCL8 等趋化因子的分泌，以抵消巨噬细胞的招募。随后，交联的 DIP 被释放，通过 CCR2/JAK2/STAT3 级联信号通路触发肿瘤相关巨噬细胞 (TAM) 向免疫刺激 M1 表型极化。 3BP@DIPPGel 的这种双重作用可恢复肿瘤细胞的免疫原性，高效并激活免疫细胞。此外，基于 3BP@DIPPGel 的化学免疫疗法上调了唾液酸结合 Ig 样凝集素 10 的表达，从而使荷瘤小鼠的肿瘤对抗 CD24 疗法敏感。因此，该策略在预防肿瘤转移和复发方面具有巨大潜力。据我们所知，这项研究开创性地展示了糖酵解抑制剂诱导的肿瘤焦亡，它可以与 DIP 介导的 TAM 极化有效协调以实现免疫激活，为差异化持续药物递送以促进癌症免疫治疗提供了新的范例.版权所有 © 2024。由 Elsevier B.V. 出版

In the realm of combined cancer immunotherapy, the strategic combination of therapeutics targeting both cancer cells and macrophages holds immense potential. However, the major challenges remain on how to achieve facile spatiotemporal delivery of these therapies, allowing ease of manipulation and ensuring differential drug release for enhanced synergistic therapeutic effects. In the present study, we introduced a tumor microenvironment (TME)-adapted hydrogel with the phenylboronic acid-modified dipyridamole prodrug (DIPP) as a crosslinker. This prodrug hydrogel scaffold, 3BP@DIPPGel, could be formed in situ by a simple mixture of DIPP and poly(vinyl alcohol) (PVA), and loaded with a high ratio of 3-bromopyruvic acid (3BP). The 3BP@DIPPGel enables spatiotemporal localized delivery of dipyridamole (DIP) and 3BP with distinct release kinetics that effectively reshape the immunosuppressive TME. Upon reactive oxygen species (ROS) stimulation, 3BP@DIPPGel preferentially released 3BP, inducing tumor-specific pyroptosis via the ROS/BAX/caspase-3/GSDME signaling pathway and decreasing the secretion of chemokines such as CCL8 to counteract macrophage recruitment. Subsequently, the crosslinked DIP is released, triggering the tumor-associated macrophages (TAMs) polarization towards the immunostimulatory M1 phenotype via the CCR2/JAK2/STAT3 cascade signaling pathway. This dual action from 3BP@DIPPGel leads to the restoration of tumor cell immunogenicity with high efficacy and activation of immune cells. Furthermore, the 3BP@DIPPGel-based chemoimmunotherapy upregulates the expression of sialic-acid-binding Ig-like lectin 10 and hence sensitizing tumors to anti-CD24 therapy in the tumor-bearing mice. Therefore, this strategy can have significant potential in the prevention of tumor metastases and recurrence. To the best of our understanding, this study represents a pioneering showcase of tumor pyroptosis, induced by glycolytic inhibitors, which can be effectively coordinated with DIP-mediated TAM polarization for immune activation, offering a new paradigm for differentially sustained drug delivery to foster cancer immunotherapy.Copyright © 2024. Published by Elsevier B.V.